Pyrrolo[2,3-d] pyrimidine compounds are potent inhibitors of protein kinase, such as the enzyme Janus Kinase 3 (JAK 3), and are therefore useful in the treatment of a wide range of autoimmune disorders such as lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type 1 diabetes and the complications thereof, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerating colitis, Crohn's disease, Alzheimer's disease and leukaemia. Said compounds are also useful in the treatment and prevention of rejection following organ transplant.
Tofacitinib citrate (I) (FIG. 1) is an active ingredient belonging to the class of Janus Kinase inhibitors. It is currently used in the treatment of rheumatoid arthritis, and under study for the treatment of psoriasis and other autoimmune disorders.
The preparation of tofacitinib (II) and the monocitrate salt I thereof was disclosed for the first time in WO2001/042246, wherein intermediate VI is obtained with the method of direct condensation between VII and VIII. Through hydrogenation of VI, the amino position of the piperidine residue is deprotected to obtain intermediate V, which can then be N-acylated with cyanoacetic acid or derivatives thereof to give firstly tofacitinib free base (intermediate II), and finally I after salification with citric acid. The structures of said intermediates are reported in FIG. 1.
Said document does not give any indications about the stereochemistry of the intermediates or the product. The process presented in WO2001/042246 involves a number of drawbacks, especially the fact that product I is obtained with a total molar yield of 6%. Moreover, for the first step, namely condensation between VII and VIII to give intermediate VI, the operational procedure involved is difficult to implement on an industrial scale; condensation is performed using triethylamine as solvent, and a pressure sufficient to enable the mixture to reach 100° C. is applied; the product is only obtained after a 3-day reaction, and isolation by silica-gel column chromatography.
Purification by silica-gel column chromatography is also required to isolate the next intermediate (intermediate V).
WO0209/6909 describes the same synthesis route, albeit with some procedural variations, but with precise references to the stereochemistry of the intermediates involved (Scheme 1).
Here, intermediate VIII is first resolved to give optically active IX, and only at this point is it condensed with intermediate VII to give X, which is also optically active; this process produces tofacitinib citrate (I) with high enantiomeric purity.
However, said process has some critical factors, especially the fact that one of the two methods proposed for resolution of VIII involves the use of an expensive resolving agent (phencyphos). Moreover, in the condensation between VII and IX, intermediate X is obtained in a low yield (54%), and purification by silica gel column chromatography is required to isolate the next intermediate (intermediate III).

WO2007/012953 discloses two alternative synthesis processes wherein intermediate VII is activated in one case by the presence of a tosyl group and in the other by a chlorine atom.
The first process (Scheme 2) can be summarised as follows:
1. Activation of VII to give intermediate XI
2. Resolution of VIII to give IX
3. Condensation between intermediate XI and intermediate IX to give intermediate XII
4. Removal of activating group from XII to give intermediate X
5. Hydrogenation of intermediate X to give intermediate III
6. N-acylation reaction of intermediate III to piperidine nitrogen to give intermediate II (tofacitinib)
7. Salification of intermediate II to give tofacitinib monocitrate (I)
Although this process provides a significant increase in global molar yield (18-20 percentage points), it involves two more synthesis steps than the process illustrated in WO02/096909. Moreover, document WO2007/012953 describes an alternative method of obtaining compound IX with high enantiomeric purity which, although it is innovative compared with the resolution of VIII to give IX already described in WO02/096909, is particularly onerous, especially if applied on a large scale, because it involves the use of an expensive rhodium-based catalyst during the asymmetrical reduction of the pyridine ring of VIII to give IX.

The second process (Scheme 3) can be summarised as follows:
1. Resolution of VIII to give IX
2. Condensation between intermediate XIII and intermediate IX to give intermediate XIV
3. Hydrogenation of intermediate XIV to give intermediate III
4. N-acylation reaction of intermediate III to give intermediate II
5. Salification of intermediate II to give tofacitinib monocitrate (I)

In this process the number of steps is limited and the global molar yield is high; however, the main drawback thereof is represented by the use of a raw material (compound XIII) which is much more expensive than the one used in the other processes (compound VII).
There is consequently still a need to find a synthesis route which is industrially scalable and gives tofacitinib with higher yields and purity.
The present patent application therefore illustrates an alternative method of obtaining intermediate III with no need to resolve VIII.